Prof. Gao Chengjiang's Group Discovered a Novel Regulatory Mechanism of Innate Antiviral Immunity
Source：Gao Chengjiang
2017-03-07
Recently, Prof. Gao Chengjiang from Shandong University has published a paper in Nature Immunology about the regulation of innate antiviral immunity by the E3 ubiquitin ligase TRIM31 (Liu Bingyu, et al., TRIM31 promotes MAVS aggregation and activation through K63-linked polyubiquitination. Nat Immunol. 2017 Feb;18(2):214-224.).
The innate immune response provides the first line of defense against invading pathogens. Activation of the innate immune response requires the pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs) and intracellular DNA sensors. RIG-I and MDA5 are cytosolic RNA sensors that detect viral RNA in the cytosol. Activation of RIG-I and MDA5 by RNA virus results in the recruitment of the adaptor protein MAVS (also known as IPS1, VISA or Cardif) to the RLR signalsome, leading to the activation of TBK1/IKKi and IRF3 for Type I IFNs production. Type I IFNs further activate downstream signaling pathways that lead to transcriptional induction of a wide range of antiviral genes. The antiviral gene products collaborate to elicit cellular antiviral response through various mechanisms. MAVS is a very important adaptor localized to mitochondria to exert its function in this process. However, the detailed molecular mechanisms for MAVS aggregation and activation are not clear.
In this paper, the authors identified a mitochondria-localized TRIM family protein TRIM31 as a positive regulator of MAVS. TRIM31 knockdown or deficiency attenuated innate antiviral response against RNA virus infection in vitro and in vivo. TRIM31 interacted with and promoted K63-linked polyubiquitination of MAVS on lysine 10, 311 and 461. Importantly, TRIM31-mediated K63-linked polyubiquitination facilitated the formation of prion-like MAVS aggregates to activate antiviral innate immune response. This study revealed new insights in the molecular regulation of MAVS aggregation and cellular antiviral response through TRIM31-mediated K63-linked polyubiquitination of MAVS.
Ph.D. student Liu Bingyu and Dr. Zhang Meng from SDU are the co-first authors of this paper. Dr. Gao Chengjiang from the School of Basic Medical Sciences of SDU is the corresponding author. This work was supported by grants from the Natural Science Foundation of China.
The innate immune response provides the first line of defense against invading pathogens. Activation of the innate immune response requires the pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs) and intracellular DNA sensors. RIG-I and MDA5 are cytosolic RNA sensors that detect viral RNA in the cytosol. Activation of RIG-I and MDA5 by RNA virus results in the recruitment of the adaptor protein MAVS (also known as IPS1, VISA or Cardif) to the RLR signalsome, leading to the activation of TBK1/IKKi and IRF3 for Type I IFNs production. Type I IFNs further activate downstream signaling pathways that lead to transcriptional induction of a wide range of antiviral genes. The antiviral gene products collaborate to elicit cellular antiviral response through various mechanisms. MAVS is a very important adaptor localized to mitochondria to exert its function in this process. However, the detailed molecular mechanisms for MAVS aggregation and activation are not clear.
In this paper, the authors identified a mitochondria-localized TRIM family protein TRIM31 as a positive regulator of MAVS. TRIM31 knockdown or deficiency attenuated innate antiviral response against RNA virus infection in vitro and in vivo. TRIM31 interacted with and promoted K63-linked polyubiquitination of MAVS on lysine 10, 311 and 461. Importantly, TRIM31-mediated K63-linked polyubiquitination facilitated the formation of prion-like MAVS aggregates to activate antiviral innate immune response. This study revealed new insights in the molecular regulation of MAVS aggregation and cellular antiviral response through TRIM31-mediated K63-linked polyubiquitination of MAVS.
Ph.D. student Liu Bingyu and Dr. Zhang Meng from SDU are the co-first authors of this paper. Dr. Gao Chengjiang from the School of Basic Medical Sciences of SDU is the corresponding author. This work was supported by grants from the Natural Science Foundation of China.
